Compounds of the cyclopentanopolyhydrophenanthrene series and a method of making thesame



Patented July 22, 1941 COMPOUNDS OF THE CYCLOPENTANOPOLY- HYDROPHENANTHRENE SERIES AND A METHOD .OF MAKING THE SAME Elisabeth Dane, Munich, Germany, assignor to Schering Corporation, Bloomfield, N. J., a cor-- poration of New Jersey No Drawing. Application October 26, 1938, Serial No. 237,144. In Germany October 27, 1937 12 Claims.

This invention relates to compounds of the cyclopentano phenanthrene series and more particularly to compounds of the oestrane series and a method of making the same.

During the last year a number of scientists have studied the synthesis of the cyclopentano phenanthrene system from simple compounds; compare, for instance, Robinson and coworkers, J ournal of the Chemical Society, London, 1936 and 1937.

Recently a publication of Dane and coworkers (Annalen der Chemie, vol. 532, page 4%, 1937) has become known wherein synthetic reactions using tetralone or methoxytetralone as starting material are described for the purpose of building up the cyclopentano phenanthrene four-ring system,- without, however, achieving this goal.

In the copending applications Serial No. 207,- 061, filed on May'10, 1938, and entitled Hydrogenated indane-diones and a method of producing the same and Serial No. 232,087, filed on September 28, 1938, and entitled Naphthalene derivatives and a method of producing the same there are described methods whereby compounds of the cyclopentano phenanthrene series can be obtained. For this purpose one proceeds in such a manner that ethinylor vinyl-dihydro naphthalene compounds and their derivatives are combined with philodienic compounds; thus from l-vinyl-3,4-dihydro-G-methoxy-naphthalene and methyl cyclopentenedione hydroxy diketo oestratetraene compounds are obtained.

Now, I have found, that valuable compounds can be produced when transforming such diketo compounds if necessary after saturation of the non-aromatic double bonds that may be present in the ring system, into the corresponding diols or monoketones which in their constitution are similar to or like. oestriol or oestrone compounds or isomeric therewith.

In order to carry out the reaction according to this invention one proceeds in such a manner that the diketo compound is subjected to a hydrogenation process whereby a mixture of oestriol compounds is obtained. By splitting off water from these oestriols the corresponding oestronelike compounds can be produced.

As starting materials for the present invention there may be used especially compounds of the following formula X =0 I o D 0 l A H B I Y In this formula R represents a hydroxy group or a group that can be transformed into the hydroxy group such as an ether-, ester-group, halogen or the like, while X and Y are either hydrogen or a methyl residue. The two carbonyl groups can be present at any place in the ring D. Furthermore, the compounds can be unsaturated in ring 0, for instance, there may be used compounds that are obtained by diene-synthesis from 1 vinyl 3,4 dihydro-B-methoxy naphthalene and methyl cyclopentenedione. The reduction of the keto group to the corresponding alcohol group can be carried out I have found by means of the usual reduction agents, such as, for instance, by means of catalytic hydrogenation in the presence of customary hydrogenation catalysts, by treating the starting material with a hydroxy group by means of compounds containing the latter group according to the method of- Meerwein-Schmidt and Ponndorf, by phyto chemical methods, or the like.

If it is intended to saturate a double bond present in ring C the use of catalytic reduction method is advisable.

The splitting off of water from the diols formed by reduction of the diketones in order to produce monoketones is carried out in the customary manner, for instance, by treatment with sulphuric acid, zinc chloride, by distillation and the like.

Likewise the reforming of the hydroxyl group is carried out in a customary manner. If possible, the splitting off of water may be combined with the reforming of the hydroxyl group.

The purification of the reaction products obtained can be carried out by chemical or physical methods known per se. Thus, the diols or monoketones can be purified by distillation, recrystallisation, adsorption on aluminum oxide and the like or by any other known method. A preferable method of purification consists in con- \eIt-illg the reaction products into derivatives such as by means of the known ketone reagents, for instance, by means of semi-carbazide, Girard reagent and the like.

MethoXy-diketo-oestratetraene as it is obtained, for instance, by diene synthesis of methoxy vinyldihydronaphthalene with methyl cyclopentenedione is subjected in alcoholic solution to the action of hydrogen in the presence of the so-called Rupe catalyst until 3 mols of hydrogen are taken up. After removing the catalyst the reduction product is heated with about 100 fold its amount of hydrogen bromide-glacial acetic acid solution for 3 hours to boiling. Thereupon it is evaporated in a vacuum almost to dryness and the residue is dissolved in dilute sodium hydroxide solution while heating. From the filtered solution after acidification, the phenolic portion is obtained by extraction with ether. In order to complete the splitting off of the water the phenols may be subjected to a distillation in a high vacuum above potassium hydrosulfate. The reaction of the phenolic portion with semicarbazide yields a difficultly soluble semi-carbazone or a mixture of semicarbazones that have the composition of an oestrone semi-carbazone. This is split up in the customary manner to yield a monoketone of the cyclopentano polyhydro phenanthrene series.

Of course, many other changes and variations may be made in the reaction conditions, the starting materials, the solvents and reagents used as is known to those skilled in the art and in accordance with the principles set forth herein and the claims annexed hereto.

What I claim is:

1. A method for producing compounds of the estrane series, comprising subjecting a di-keto compound of the group consisting of saturated C-ring and unsaturated C-ring compounds of the cyclopentano polyhydro phenanthrene series whose composition, except for the double bond in the C-ring in the case of the unsaturated C-ring compounds, is represented by the formula wherein R represents a member selected from the class consisting of a hydroxyl group and groups transformable into the hydroxyl group with the aid of hydrolysis, while X and Y are members of the group consisting of hydrogen and methyl residue, which keto compounds have the two keto groups at any position in ring D, to the action of a reducing agent until the keto groups are reduced, whereby diol compounds of the oestrane series are obtained.

2. Method as set forth in claim 1, wherein the produced diol compounds are treated with an agency capable of splitting the elements of water from the two hydroxyl groups at the ring D, whereby mono-ketones are formed.

3. A method according to claim 1, wherein the reduction is carried out by means of catalytically activated hydrogen.

4. A method according to claim 1, wherein as starting material there is employed a di-keto oestratetraene compound substituted at the 3-position with a group transformable with the aid of hydrolysis into a hydroxyl group, wherein the produced diol compounds are treated with an agency for splitting the elements of water from the two hydroxyl groups of the ring D, and wherein the substituent at the 3-position is thereafter transformed into a hydroxyl group.

5. A method according to claim 1, wherein as starting material there is employed a di-keto oestratetraene compound substituted at the 3-position with a group transformable with the aid of hydrolysis into a hydroxyl group, and wherein the produced diol compounds are treated with 'an agency for simultaneously splitting the elements of water from the two hydroxyl groups at the ring D and simultaneously transforming the substituent at the position 3 into a hydroXyl group.

6. A method according to claim 1, wherein as starting material there is employed a 3-ether di-keto oestratetraene compound, and wherein the produced diol compounds are treated with an agency for splitting the elements of water from the two hydroxyl groups at the ring D and simultaneously transforming the substituent at the 3-p0siti0n into a hydroxyl group.

7. A method according to claim 1, wherein as starting material there is employed a 3-methoxy di-keto oestratetraene compound, and wherein the produced diol compounds are treated with an agency for splitting the elements of water and for simultaneously transforming the substituent at the 3 position into a hydroxyl group. i

8. A method according to claim 1, wherein the produced diol compounds are treated with a mixture of hydrobromic acid and glacial acetic acid to split the elements of water from the two hydroxyl groups at the ring D.

9. A method according to claim 1, wherein R is a group which is convertible into an hydroxyl group with the aid of hydrolysis, and including the step of replacing R with an hydroxyl group.

10. A method according to claim 1, wherein R is a group which is convertible into an hydroxyl group with the aid of hydrolysis, and including the steps of treating the diol compounds with an agency capable of splitting off the elements of water from the two formed hydroXyl groups, and replacing R with an hydroxyl group.

11. A method according to claim 1, wherein the starting compound is a 3-hydroXy-diketooestratetraene.

12. A method according to claim 1, wherein the starting compound is a B-methoxy-diketooestratetraene.

ELISABETH DANE. 

